US9365653B2ActiveUtilityA1

Human PAC1 antibodies

95
Assignee: AMGEN INCPriority: Mar 15, 2013Filed: Jun 13, 2014Granted: Jun 14, 2016
Est. expiryMar 15, 2033(~6.7 yrs left)· nominal 20-yr term from priority
Inventors:Cen XuAgnes Eva Hamburger
A61P 25/06C07K 2317/24C07K 16/2869C07K 2317/21C07K 2317/76C07K 2317/41C07K 2317/565C07K 16/28C07K 2317/92C07K 2316/96
95
PatentIndex Score
24
Cited by
53
References
27
Claims

Abstract

Antibodies and antigen-binding fragments thereof that bind to human PAC1 are provided. Nucleic acids encoding the antibodies and antigen-binding fragments thereof, vectors, and cells encoding the same are also provided. The antibodies and antigen-binding fragments thereof can inhibit binding of PAC1 to PACAP, and are useful in a number of PAC1 related disorders, including the treatment and/or prevention of headache disorders, including migraine.

Claims

exact text as granted — not AI-modified
The invention claimed is: 
     
       1. An isolated antibody or antigen-binding fragment thereof that specifically binds human pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1), comprising (i) a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, and (ii) a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein CDRH1 comprises the sequence of SEQ ID NO: 165, CDRH2 comprises the sequence of SEQ ID NO: 179, CDRH3 comprises the sequence of SEQ ID NO: 189, CDRL1 comprises the sequence of SEQ ID NO: 139 or SEQ ID NO: 140, CDRL2 comprises the sequence of SEQ ID NO: 151, and CDRL3 comprises the sequence of SEQ ID NO: 157. 
     
     
       2. The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein CDRL1 comprises the sequence of SEQ ID NO: 140. 
     
     
       3. The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein CDRL1 comprises the sequence of SEQ ID NO: 139. 
     
     
       4. The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the light chain variable region comprises (i) the amino acid sequence of SEQ ID NO: 78 or SEQ ID NO: 80, (ii) an amino acid sequence at least 90% identical to an amino acid sequence of SEQ ID NO: 78 or SEQ ID NO: 80, or (iii) an amino acid sequence at least 95% identical to an amino acid sequence of SEQ ID NO: 78 or SEQ ID NO: 80; and the heavy chain variable region comprises (i) an amino acid sequence selected from SEQ ID NOs: 108, 110, or 112, (ii) an amino acid sequence at least 90% identical to an amino acid sequence selected from SEQ ID NOs: 108, 110, or 112, or (iii) an amino acid sequence at least 95% identical to an amino acid sequence selected from SEQ ID NOs: 108, 110, or 112. 
     
     
       5. The isolated antibody or antigen-binding fragment thereof of  claim 4 , wherein:
 (a) the light chain variable region comprises the sequence of SEQ ID NO: 78 and the heavy chain variable region comprises the sequence of SEQ ID NO: 108; 
 (b) the light chain variable region comprises the sequence of SEQ ID NO: 80 and the heavy chain variable region comprises the sequence of SEQ ID NO: 110; 
 (c) the light chain variable region comprises the sequence of SEQ ID NO: 80 and the heavy chain variable region comprises the sequence of SEQ ID NO: 112; and 
 (d) the light chain variable region comprises the sequence of SEQ ID NO: 78 and the heavy chain variable region comprises the sequence of SEQ ID NO: 112. 
 
     
     
       6. The isolated antibody or antigen-binding fragment thereof of  claim 5 , wherein the light chain variable region comprises the sequence of SEQ ID NO: 80 and the heavy chain variable region comprises the sequence of SEQ ID NO: 110. 
     
     
       7. The isolated antibody or antigen-binding fragment thereof of  claim 5 , wherein the light chain variable region comprises the sequence of SEQ ID NO: 78 and the heavy chain variable region comprises the sequence of SEQ ID NO: 112. 
     
     
       8. The isolated antibody or antigen-binding fragment thereof of  claim 1 , comprising (A) a light chain comprising (i) the sequence of SEQ ID NO: 6 or SEQ ID NO: 8, (ii) a sequence at least 90% identical to a sequence of SEQ ID NO: 6 or SEQ ID NO: 8, or (iii) a sequence at least 95% identical to a sequence of SEQ ID NO: 6 or SEQ ID NO: 8; and (B) a heavy chain comprising (i) a sequence selected from SEQ ID NOs: 38, 40, 42, or 44, (ii) a sequence at least 90% identical to a sequence selected from SEQ ID NOs: 38, 40, 42, or 44, or (iii) a sequence at least 95% identical to a sequence selected from SEQ ID NOs: 38, 40, 42, or 44. 
     
     
       9. The isolated antibody or antigen-binding fragment thereof of  claim 8 , comprising a light chain comprising the sequence of SEQ ID NO: 6 and a heavy chain comprising the sequence of SEQ ID NO: 38. 
     
     
       10. The isolated antibody or antigen-binding fragment thereof of  claim 8 , comprising a light chain comprising the sequence of SEQ ID NO: 8 and a heavy chain comprising the sequence of SEQ ID NO: 40. 
     
     
       11. The isolated antibody or antigen-binding fragment thereof of  claim 8 , comprising a light chain comprising the sequence of SEQ ID NO: 8 and a heavy chain comprising the sequence of SEQ ID NO: 42. 
     
     
       12. The isolated antibody or antigen-binding fragment thereof of  claim 8 , comprising a light chain comprising the sequence of SEQ ID NO: 8 and a heavy chain comprising the sequence of SEQ ID NO: 44. 
     
     
       13. The isolated antibody or antigen-binding fragment thereof of  claim 8 , comprising a light chain comprising the sequence of SEQ ID NO: 6 and a heavy chain comprising the sequence of SEQ ID NO: 44. 
     
     
       14. The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof is selected from the group consisting of a monoclonal antibody, a Fab fragment, an Fab′ fragment, an F(ab′)2 fragment, an Fv fragment, a diabody, and a single chain antibody. 
     
     
       15. The isolated antibody or antigen-binding fragment thereof of  claim 14 , wherein the isolated antibody is a monoclonal antibody selected from the group consisting of a fully human antibody, a humanized antibody and a chimeric antibody. 
     
     
       16. The isolated antibody or antigen-binding fragment thereof of  claim 15 , wherein the monoclonal antibody is an IgG1-, IgG2-, IgG3-, or IgG4-type antibody. 
     
     
       17. The isolated antibody or antigen-binding fragment thereof of  claim 16 , wherein the monoclonal antibody is an aglycosylated IgG1 antibody. 
     
     
       18. The isolated antibody or antigen-binding fragment thereof of  claim 17 , wherein the monoclonal antibody has an N297G mutation in its heavy chain. 
     
     
       19. The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof selectively inhibits human PAC1 relative to human VPAC1 and human VPAC2. 
     
     
       20. An isolated polynucleotide that encodes an antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
       21. The isolated polynucleotide of  claim 20 , wherein the polynucleotide comprises a sequence selected from SEQ ID NOs: 5, 7, 37, 39, 41, or 43. 
     
     
       22. The isolated polynucleotide of  claim 20 , wherein the polynucleotide comprises a sequence selected from SEQ ID NOs: 77, 79, 107, 109, or 111. 
     
     
       23. An expression vector comprising an isolated nucleic acid or polynucleotide encoding an antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
       24. A cell line transformed with the expression vector of  claim 23 . 
     
     
       25. A method of making an antibody or antigen binding fragment thereof that specifically binds human PAC1, comprising preparing the antibody or antigen binding fragment thereof from the cell line of  claim 24  that secretes the antibody or antigen binding fragment thereof. 
     
     
       26. A pharmaceutical composition comprising an antibody or antigen binding fragment thereof of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
       27. The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof of  claim 1  specifically binds to human PAC1 with an equilibrium binding affinity of less than 1 nM.

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